The incidence of hepatocellular carcinoma (HCC) is increasing dramatically in the US and globally, and accounts for more than 600,000 deaths/year. Cirrhosis of the liver, whether chemically or virally induced, is the major predisposing factor to the development of HCC. Chronic alcohol consumption has been identified as a significant risk factor in patients developing cirrhosis and progression to HCC, both in its own right and as a synergistic factor following viral or chemical insult. Advances in our understanding of the cellular and biochemical pathways affected following alcohol ingestion have identified ethanol metabolism (and associated reactive oxygen species (ROS) generation/oxidative stress) as a major factor in mediating the deleterious effects of alcohol in the liver and other organs. These findings have led to the proposed use of systemic antioxidants to inhibit the development and progression of several hepatic diseases including HCC. These studies have led to the emergence of S-adenosyl methionine (SAMe) as a potential therapeutic agent. While efficacious in rodent models, there is increasing concern regarding its effectiveness in human clinical trials. For several millennia natural antioxidants have been used in the treatment of liver disease. Despite their over-the-counter availability relatively little is known about their efficacy and mechanisms of action. Previous studies by our laboratory demonstrate a central role for G-proteins in mediating mitogenesis in HCC in vitro. Furthermore, treatment with alcohol enhances these pro-mitogenic pathways. While considerable research has identified important events during hepatic cell transformation in the setting of chronic alcohol consumption, relatively little is known about the effects of alcohol on the rate of HCC progression in livers predisposed to tumor formation. The current proposal hypothesizes that chronic alcohol consumption increases the rate and incidence of foci development and HCC progression. To test this hypothesis studies will be performed using in vivo murine models of progressive foci development and HCC progression in animals undergoing chronic alcohol consumption. In addition this proposal will address the mechanistic effects by which silibinin, a commonly used flavanoid derived from the milk thistle plant, acts to inhibit the rate of tumor progression in a clinically relevant model of HCC in the absence and presence of chronic alcohol intake. Specifically, these studies will focus on identifying the role of specific, pro-mitogenic signaling cascades demonstrated to be important in HCC proliferation that are affected by alcohol treatment in vitro. Given the widespread use and abuse of alcohol in society, and concerns regarding the efficacy of current therapeutic agents for the treatment of HCC, we believe it is imperative to explore alternative approaches. While widely available, and anecdotally effective, little is understood about the mechanisms of action of plant- derived antioxidants in the treatment of hepatic disease.